Our long term goal is to widespread the use of PPF technology for promoting effective production of drug-encapsulating microparticles with uniform size and physical characteristics that can be leveraged to release a specific drug at controlled rates over multi-day periods in vivo after a single administration. For this proposal, we are specifically targeting a cost and dose-effective management of chronic pain with precisely tailored drug release characteristics. Chronic pain afflicts a large population in United States. Extended release formulations of safer (unscheduled) opioids can improve patient compliance and drug efficacy, and can limit the possibility of breakthrough pain, all without putting the patients at the risk of addiction. However, existing extended release opioid formulations are insufficient, and are limited to providing relief up to a maximum of 24 h. Using tramadol, an unscheduled opioid, this project aims to create a long-acting (up to 5-day) tramadol formulation in an injectable form to enhance pain relief and fill a critical innovation gap in the pharmaceutical market. The specific objective of this application is to optimize tramadol-loaded microspheres produced by PPF technology with a 5 day zero-order drug release profiles, imitating a constant infusion pump-like dosing (Specific Aim 1), and validate the results achieved with extended release formulations of tramadol in vivo (Specific Aim 2). Our overall hypothesis is that extended pain management therapy developed using uniform microspheres produced by PPF technology will offer a cost and dose-effective management of chronic pain with precisely tailored drug release characteristics, which will provide a more controlled and predictable drug release compared to tramadol-loaded microspheres fabricated using conventional methods, and significantly improve controlled release characteristics compared to contemporary commercially-available sustained-release pain management products (e.g., ULTRAM(R)). Multi-day chronic pain management therapy holds the potential to provide a revolutionary alternative for pain management. PUBLIC HEALTH RELEVANCE: Chronic pain afflicts a large population in United States. Extended release formulations of safer (unscheduled) opioids can improve patient compliance and drug efficacy, and can limit the possibility of breakthrough pain, all without putting the patients at the risk of addiction. However, existing extended release opioid formulations are insufficient, and are limited to providing relief up to a maximum of 24 h. Using tramadol, an unscheduled opioid, this project aims to create a long- acting (up to 5-day) tramadol formulation in an injectable form to enhance pain relief and fill a critical innovation gap in the pharmaceutical market.